new anticoagulants when and why should i use them
play

Winship Cancer Institute of Emory University New Anticoagulants: When and Why Should I Use Them? Christine L. Kempton, MD, MSc Associate Professor of Pediatrics and Hematology and Medical Oncology Hemophilia of Georgia, Inc , Directors Chair in

0 downloads 3 Views 237 KB Size Report
  1. Winship Cancer Institute of Emory University New Anticoagulants: When and Why Should I Use Them? Christine L. Kempton, MD, MSc Associate Professor of Pediatrics and Hematology and Medical Oncology Hemophilia of Georgia, Inc , Directors Chair in Hemostasis Disclosures • Nothing relevant to disclose. 1

  2. Venous Thromboembolism (VTE) • Overall annual incidence 1/1000 persons • Increases with age: 5/1000 persons annually in people over 80 years of age • Location • Pulmonary embolism (PE) – 2/3 • Deep venous thrombosis (DVT) – 2/3 • Mortality within one month of diagnosis: • DVT – 6% • PE – 12% • Long-term complications • DVT- post-thrombotic syndrome occurs in 20-50% • PE- chronic pulmonary hypertension occurs in 2-4% Yeh et al. Blood 2014 pre-published Old Oral Anticoagulants: Warfarin • First approved for medical use in 1954 • Inhibits vitamin K reductase (VKOR) • Prevents  carboxylation of clotting factors II, VII, IX, and X • Partially decarboxylated proteins have less clotting activity • Metabolised by cytochrome P450 (CYP) • particularly CYP2C9 • Limitations: • Food-drug interactions • Drug-drug interactions • Delayed onset of action • Variability of response  monitoring • Safety and efficacy dependent on therapeutic INR Hirsh et al. Circulation 2003; 107: 1692-1711 2

  3. Novel Oral Anticoagulants (NOAC) Factor XIa Factor VIIIa Factor VIIa Factor IX Factor IXa Tissue Factor Factor Va Rivaroxaban Factor X Factor Xa Apixiban Edoxaban Thrombin Dabigitran Prothrombin Fibrinogen Fibrin 4 Dabigitran Rivaroxaban Apixiban Edoxaban Target Thrombin Factor Xa Factor Xa Factor Xa Pro-drug Yes No No No Elimination 14-17 hrs 7-11 hrs 8-14 hrs 5-11 hrs half-life Bioavailability 3-7 80 66 45 % Protein 35 >90 ~85 40-59 Binding % Route of Urine ~80%, Urine ~66%, Urine ~25%, Urine ~35% elimination feces ~20% feces ~30% feces ~70% Feces ~60% Dosing Twice/day Once/day* Twice/day Once/day Substrate of No Yes (CYP3A4, Yes Yes CYP enzymes CYP2J2) (CYP3A4) (CYP3A4) Substrate of Yes Yes Yes Yes P-glycoprotein 3

  4. Indications for Use Non- VTE Initial VTE VTE valvular prevention Treatment Secondary A. Fib Prevention Dabigitran + - + (after 5-10 days + of parenteral AC) Rivaroxaban + + + + Apixiban + + * * Edoxaban * - * (after 5-10 days of * parenteral AC) *FDA application pending Treatment of Acute VTE: Efficacy VTE Recurrence HR (95% CI) NOAC Warfarin Dabigitran- RE-COVER 2.4% 2.1% 1.10 (0.65-1.84) Study 1 ; n=1274 Rivaroxaban-EINSTEIN 2.1% 3.0% 0.68 (0.44-1.04) Study 2 ; n=3449 Rivaroxaban-EINSTEIN 2.1% 1.8% 1.12 (0.75-1.68) PE Study 3 ; n=4832 Apixiban-AMPLIFY 2.3% 2.7% 0.84 (0.60-1.18) Study 4 ; n=5244 Edoxaban-Hokusai-VTE 3.2% 3.5% 0.89 (0.70-1.13) Study 5 ; n=4921 1. Schulman et al. NEJM. 2009;361:2342-52 4. Agnelli et al. NEJM 2013; 1369:799-808 2. EINSTEIN Investigators. NEJM 2010;363:2499-510 5. Houkusai VTE Investigators. NEJM 2013;369:1406-15 3. EINSTEIN PE Investigators NEJM 2012;366:1287-97 4

  5. Treatment of Acute VTE: Safety Major Bleeding Clinically Relevant Non-Major Bleeding NOAC Warfarin HR NOAC Warfarin HR (95% CI) (95% CI) Dabigitran- RE-COVER 1.6% 1.9% 0.82 (0.45- 4.0% 7.8% - Study 1 ; n=1274 1.48) Rivaroxaban-EINSTEIN 1.8% 1.2% 0.65 (0.33- 7.3% 7.0% - Study 2 ; n=3449 1.30) Rivaroxaban-EINSTEIN PE 1.1% 2.2% 0.49 (0.31- 9.5% 9.8% - Study 3 ; n=4832 0.79) Apixiban-AMPLIFY study 4 ; 0.6% 1.8% 0.31* (0.17- 3.8% 8.0% 0.48 n=5244 0.55) (0.38-0.60) Edoxaban-Hokusai-VTE 1.4% 1.6% 0.84 (0.59- 8.1% 8.6% - study 5 ; n=4921 1.21) *p <0.001 4. Agnelli et al. NEJM 2013; 1369:799-808 1. Schulman et al. NEJM. 2009;361:2342-52 2. EINSTEIN Investigators. NEJM 2010;363:2499-510 5. Houkusai VTE Investigators. NEJM 2013;369:1406-15 3. EINSTEIN PE Investigators NEJM 2012;366:1287-97 Dabigitran Apixiban Rivaroxaban Dabigitran Apixiban Rivaroxaban Dentali F, Circulation 2012;126:2381-2391 5

  6. Secondary Prevention of VTE: Efficacy VTE Recurrence HR (95% CI) NOAC Placebo Dabigitran-RE-MEDY & 1.8% 5.6%* 0.08 (0.02-0.25) RE-SONATE 1 ; n=2856 1.3% 7.1% 0.18 (0.09-0.39) Rivaroxaban-EINSTEIN Study 2 n=1196 Apixiban-AMPLIFY EXT 3 ; 1.7%^ 8.8% 0.19 (0.11-0.33) 2.5mg n=2482 *Warfarin treated group1.3%, HR 1.44 (95% CI 0.78-2.64) ^Apixiban 2.5 mg and 5.0 mg similar 1. Schulman et al. 2013;368:709-18 2. EINSTEIN Investigators. NEJM 2010;363:2499-510 3. Agnelli et al. NEJM 2013; 1369:799-808 Secondary Prevention of VTE: Safety Major Bleeding Clinically Relevant Non-Major Bleeding NOAC Place HR NOAC Placebo HR bo (95% CI) (95% CI) Dabigitran-RE-MEDY 0.9% 0 - 5.0% 1.8% 2.92 (1.52- 5.60) & RE-SONATE 1 ; n=2856 0.7% 0 - 5.4% 1.2% - Rivaroxaban- EINSTEIN Study 2 n=1196 Apixiban-AMPLIFY 0.2% 0.5% 0.49 (0.09- 3.0% 2.3% 1.29** 2.64) (0.72-2.33) EXT 3 ; 2.5mg n=2482 ^Apixiban 2.5 mg and 5.0 mg similar 1. Schulman et al. 2013;368:709-18 2. EINSTEIN Investigators. NEJM 2010;363:2499-510 3. Agnelli et al. NEJM 2013; 1369:799-808 6

  7. Agnelli et al. NEJM 2013; 1369:799-808 Patient Selection Use Avoided: Use with Caution: • PE with hemodynamic • Advanced age > 75 years instability • Extremes of weight < 60 or > • Significant risk of bleeding 150 kg • Recent trauma or surgery • CrCl < 30 ml/min • Hepatic dysfunction (Child- Pugh B) • Pregnancy • Active cancer • High-risk settings such as HIT or antiphospholipid syndrome • Concurrent use of : • Strong inhibitors/inducers of CYP3A4 and P-glycoprotein 7

  8. Patients Currently on Warfarin INR Control Good Poor Lifestyle Adherence burden Low High Good Poor Limited benefit May benefit May benefit No benefit NOAC Selection • Preference for once daily vs. twice daily dosing: Favors rivaroxaban and edoxaban • Rivaroxaban should be taken with food • Ability to use an all oral regimen at diagnosis: Favors rivaroxaban and apixiban • Low renal clearance- Avoid dabigitran and favor apixiban • History of coronary artery disease— Avoid dabigitran • Upper GI complaints - Avoid dabigitran • Recent GI bleed- Favors apixiban • Clinical setting is extended treatment for secondary prevention— Favors apixiban • CYP3A4 interaction -Favors dabigitran 8

  9. Monitoring • Acute Treatment: • Early follow-up if discharged from the ED • Follow-up at times of transition (apixiban: 7 days, rivaroxaban: 21 days) • Extended Treatment • Follow-up to assess adherence, efficacy, side effects, stability of renal/liver function • Every 3-12 months, depending on renal function • Laboratory monitoring • Approved kits for rivaroxaban (anti-Xa assay) and dabigitran (anti-IIa assay) • Not recommended for routine monitoring • Potential uses: • Emergent surgery or other invasive procedure • Failure of efficacy or safety • Anticipated alterations of pharmacokinetics or pharmacodynamics Practical Issues • Switching from warfarin to NOAC: • Stop warfarin and start NOAC when INR < 2.0 • Likely after 2-3 missed doses depending on the INR at cessation of warfarin • Encourage use of Medic Alert that identifies NOAC use • Discuss importance of adherence: • Use of pill box essential • Take at similar time each day • Missed dose: • < 12 hours (daily dosing) and 6 hours (BID dosing) from missed dose, then take dose • > 12 hours (daily dosing) and 6 hours (BID dosing) from missed dose—skip the dose • Do not double up 9

  10. Bleeding Management • No reversal agent currently available, but new agents are in development Factor Xa inhibitors Direct Thrombin Inhibitors Normalization of 12-24h CrCl > 80 mL/min: 12-24h hemostasis CrCl 50-80 mL/min: 24-36h CrCl 30-50 mL/min: 36-48h CrCl < 30 mL/min: > 48h General measures Hold medication, local hemostatic measures, transfusion therapy as need for anemia and thrombocytopenia, tranexamic acid Increase clearance -- Hemodialysis Promote Prothrombin complex concentrates (PCC) (25 U/kg), hemostasis activated PCC (aPCC) (50 U/kg), or rFVIIa (90 mcg/kg)-no clinical data Heidbuchel et al. Eur Heart J 2014 pre-published Peri-operative Management • Pre-operative: Low vs. high surgical bleeding risk Dabigitran Apixiban Edoxaban Rivaroxaban Low High Low High Low High Low High CrCl > 80 mL/min > 24h > 48h > 24 h > 48h ND ND > 24 h > 48h CrCl 50-80 mL/min > 36h > 72h > 24 h > 48h ND ND > 24 h > 48h CrCl 30-50 mL/min > 72h > 120h > 24 h > 48h ND ND > 24 h > 48h ND=no data • Post-operative • Restart NOAC once full anticoagulation is allowed—likely 48-72 hours after major surgery • May need prophylactic anticoagulation with LWMH in the immediate post- operative period until able to resume full dose anticoagulation Heidbuchel et al. Eur Heart J 2014 pre-published Prescribing information 10

  11. Summary • New oral anticoagulants … • offer a real alternative to warfarin therapy for a large number of patients. • are efficacious for: • Treatment of acute VTE: DVT and hemodynamically stable PE. • Secondary prevention of recurrent VTE. • are as safe or safer than warfarin. • are more convenient and less burdensome than warfarin. • Patients not appropriate for NOACs include those with: • Severe renal or liver impairment • Cancer • Extremes of weight • Pregnant • Significantly advanced age • Strong CYP3A4 and P-gp inhibitors 11

Recommend Documents


20 2016 16 lls llsa revie iew
20 2016 16 LLS LLSA Revie iew

11/6/2017 AR ARTICLE 1 20 2016 16 LLS LLSA Revie iew

prioritizing comparative effectiveness research questions
Prioritizing Comparative Effectiveness

Prioritizing Comparative Effectiveness Research Questions for New Oral

the emerging use of novel oral
The Emerging use of Novel Oral

The Emerging use of Novel Oral Anticoagulants: Essentials for the Family

impact of anticoagulants
IMPACT OF ANTICOAGULANTS AND

IMPACT OF ANTICOAGULANTS AND ANTIPLATELET AGENTS ON LONG-TERM MORTALITY AFTER

managing patients after an anticoagulant related major
Managing Patients after an

Canadian Society of Internal Medicine Annual Meeting 2017 Managing Patients

anticoagulants to prevent recurrent placenta mediated
Anticoagulants to prevent recurrent

Anticoagulants to prevent recurrent placenta mediated pregnancy

dose finding in the cardiovascular therapeutic area the
Dose-finding in the cardiovascular

1 Dose-finding in the cardiovascular therapeutic area: The novel oral

emergency management of patients on direct oral
Emergency Management of Patients on

Emergency Management of Patients on Direct Oral Anticoagulants (DOACs) Dr

anticoagulants and bleeds
Anticoagulants and bleeds Focus on

Anticoagulants and bleeds Focus on older patients with AF Dr. Wilma Knol,

phase iii studies of direct oral
Phase III studies of direct oral

Phase III studies of direct oral anticoagulants for treatment and prevention

improving stroke prevention in patients with atrial
Improving Stroke Prevention in

Improving Stroke Prevention in Patients With Atrial Fibrillation

application for approval to manufacture esn containing
Application for approval to manufacture

Application for approval to manufacture ESN containing sodium nitrite and a

dose response assessments guidance experience expectations
Dose Response Assessments: Guidance,

Dose Response Assessments: Guidance, Experience, Expectations Vikram Sinha,

how technology assessment by hospitals differs from
How Technology Assessment by Hospitals

How Technology Assessment by Hospitals Differs from Technology Assessment by

inhibition under flow
inhibition under flow SHANNON BRIDE

A mathematical model of surface-mediated enzyme inhibition under flow

deep vein thrombosis and pulmonary embolism diagnosis and
Deep Vein Thrombosis and Pulmonary

Deep Vein Thrombosis and Pulmonary Embolism: Diagnosis and Management in the

anticoagulation
Anticoagulation Laurel Newman Quality

Anticoagulation Laurel Newman Quality implementation Manager Primary Care

updates in thrombosis
Updates in Thrombosis Dr. Ali Y.

Updates in Thrombosis Dr. Ali Y. Al-Muhaini MBBch FRCP(C) Chairman of the

showcasing
Showcasing health innovation Dr Samus

Showcasing health innovation Dr Samus ONeill Chair AHSN Network, CEO AHSN

drug spending of healthcare spending
Drug Spending % of Healthcare Spending

Drug Spending % of Healthcare Spending DRUG SPENDING % OF HEALTHCARE SPENDING

expanded mandate medicines patent pool for essential
EXPANDED MANDATE: MEDICINES PATENT

EXPANDED MANDATE: MEDICINES PATENT POOL FOR ESSENTIAL MEDICINES KEY FINDINGS

atrial fibrillation reducing the risk of stroke
Atrial fibrillation Reducing The Risk

Atrial fibrillation Reducing The Risk of Stroke Bjrn Fredriksson Arrhythmia